RABBIT CEREBRAL-CORTEX 5HT(1A) RECEPTORS

Selective 5HT(1a) agonist binding to membranes from rabbit cerebral co rtex was conceneration-dependent and saturable; the Kd was 1.1 nM and Bmax of 480 fmols/mg protein. Scatchard as well as Hill plots were lin ear; the Hill coefficient was 0.96, suggesting a single, non-interacti ng binding site. Agonist. binding was inhibited in a concentration-dep endent fashion by gamma S GTP, a result consistent with the coupling o f this binding site to the G protein signal transduction system. In co mpetition experiments involving agonist and a series of agents with kn own affinities and specificities at 5HT(1a) receptors, a rank order re lationship was found consistent with this binding site being a 5HT(1a) , binding site. Direct comparisons of agonist and antagonist binding a t rat cerebral cortex 5HT(1a) receptors and cloned human 5HT(1a) recep tors also suggested that the rabbit binding site belongs to the 5HT(1a ) class. The only rank order anomalies were with methiothepin in rabbi t cerebral cortex, where a comparatively high Ki was observed and with buspirone in cloned human 5HT(1a), receptor, where a low Ki was deter mined; these anomalies bear further study in light of the comparative pharmacology of 5HT(1a) receptors. Finally, the natural product parthe nolide was tested for affinity in the rabbit, rat, and human systems, where it uniformly was unable to displace agonist, suggesting that the 5HT(1a) receptor is not a target for this compound. Overall, these re sults suggest that a functional 5HT(1a) receptor exists in rabbit cere bral cortex. (C) 1997 Elsevier Science Inc.